1. Field of the Invention
This invention relates to 8H-pteridine-7-ones, tetrahydropteridin-7-ones, 5H,8H-pteridine-6,7-diones and pteridine-7-ureas that inhibit cyclin-dependent serine/threonine kinase, Wee 1 tyrosine kinase, and growth factor-mediated tyrosine kinase enzymes, and as such are useful to treat cell proliferation diseases and disorders. These include cardiovascular diseases including atherosclerosis and restenosis; cancer; angiogenesis; viral infections including DNA viruses such as herpes and RNA viruses such as HIV; fungal infections; type 1 diabetes and diabetic neuropathy and retinopathy; multiple sclerosis; glomerulonephritis; neurodegenerative diseases including Alzheimer's disease; autoimmune diseases such as psoriasis, rheumatoid arthritis, lupus; organ transplant rejection and host versus graft disease; Gout; polycystic kidney disease; and inflammation including inflammatory bowel disease.
2. Summary of the Related Art
Cell cycle kinases are naturally occurring enzymes involved in regulation of the cell cycle (Meijer L., “Chemical Inhibitors of Cyclin-Dependent Kinases”, Progress in Cell Cycle Research, 1995; 1:351–363). Typical enzymes include serine/threonine kinases such as the cyclin-dependent kinases (cdk) cdk1, cdk2, cdk4, cdk5, cdk6 as well as tyrosine kinases involved in cell cycle regulation such as Wee 1 kinase. Increased activity or temporally abnormal activation or regulation of these kinases has been shown to result in development of human tumors and other proliferative disorders. Compounds that inhibit cdks, either by blocking the interaction between a cyclin and its kinase partner, or by binding to and inactivating the kinase, cause inhibition of cell proliferation, and are thus useful for treating tumors or other abnormally proliferating cells.
Several compounds that inhibit cdks have demonstrated preclinical anti-tumor activity. For example, flavopiridol is a flavonoid that has been shown to be a potent inhibitor of several types of breast and lung cancer cells (Kaur, et al., J. Natl. Cancer Inst., 1992;84:1736–1740; Int. J. Oncol., 1996;9:1143–1168). The compound has been shown to inhibit cdk2 and cdk4. Olomoucine [2-(hydroxyethylamino)-6-benzylamine-9-methylpurine] is a potent inhibitor of cdk2 and cdk5 (Vesely, et al., Eur. J. Biochem., 1994;224:771–786), and has been shown to inhibit proliferation of approximately 60 different human tumor cell lines used by the National Cancer Institute (NCI) to screen for new cancer therapies (Abraham, et al., Biology of the Cell, 1995;83:105–120). More recently, the purvalanol class of cdk inhibitors have emerged as more potent derivatives of the olomoucine class of compounds (Gray, N. S., et al., Science, 1998;281:533–538).
In addition, tyrosine kinases are a class of enzymes that catalyze the transfer of the terminal phosphate of adenosine triphosphate (ATP) to tyrosine residues on protein substrates. Tyrosine kinases are essential for the propagation of growth factor signal transduction leading to cell cycle progression, cellular proliferation, differentiation, and migration. Tyrosine kinases include cell surface growth factor receptor tyrosine kinases such as FGFr and PDGFr; as well as nonreceptor tyrosine kinases, including c-src and lck. Inhibition of these enzymes have been demonstrated to cause antitumor and antiangiogenesis activity (Hamby, et al., Pharmacol. Ther., 1999;82(2–3):169–193).
Despite the progress that has been made, the search continues for small molecular weight compounds that are orally bioavailable and useful for treating a wide variety of human tumors and other proliferative disorders, including restenosis, angiogenesis, diabetic retinopathy, psoriasis, surgical adhesions, macular degeneration, and atherosclerosis. The present invention provides such compounds, their pharmaceutical formulations, and their use in treating proliferative disorders.